Abstract: Normalizing plasma glucose via intensive insulin therapy reduces the incidence of diabetic complications, but the benefits of such regimens remain limited by frequent and severe bouts of hypoglycemia. These bouts diminish the brain's capacity to detect subsequent hypoglycemia and to activate protective counterregulatory hormonal responses, with reduced glucagon and epinephrine release, thereby increasing the risk of more severe hypoglycemic events with adverse consequences including seizures, coma and permanent brain injury. Studies in older adults with type 2 diabetes have identified hypoglycemia as the major risk factor contributing to increased mortality, cardiovascular disease, falls and even dementia, highlighting the need for its diligent avoidance and individualized treatment targets. This is of particular concern in patients with longstanding type 1 diabetes (T1DM) who often have had several decades of disease exposure at a much younger age. A recent study of elderly T1DM patients found hypoglycemia unawareness and glycemic variability to be key risk factors for additional severe hypoglycemic episodes and impaired cognition, further underscoring the unmet need to comprehensively define brain adaptations to hypoglycemia and to identify preventative strategies that improve glycemic control. Using magnetic resonance spectroscopy and carbon-13 acetate both in rodent models and T1DM patients we found that enhanced brain energy substrate uptake and utilization are the hallmarks of altered brain metabolism after recurrent hypoglycemia and that increased alternate fuel levels in the brain impair hormonal counterregulation. Encouragingly, it was shown that strict avoidance of hypoglycemia via meticulous glucose control can restore hormonal responses and hypoglycemia awareness. Predictive low glucose management (PLGM) systems combine the advantages of sensor augmented pump therapy with automated basal insulin suspension to reduce hypoglycemia exposure. PLGM outperforms currently available basal insulin suspension technology for hypoglycemia prevention. However, the safety and clinical efficacy of this intervention, and the effect on counterregulation in older adults, have not been defined. Therefore the goals of this proposal are to implement a PLGM system in older T1DM patients in order to reverse brain metabolic adaptations and restore metabolic sensitivity, hypoglycemia awareness and appropriate counterregulatory hormonal responses. The ultimate purpose of our studies is to demonstrate the clinical usefulness of a technology-driven approach in older adults with T1DM to achieve tight glycemic control without exposing these particularly vulnerable patients to the risks of profound hypoglycemia. To approach this aim we have assembled a highly skilled interdisciplinary team of translational scientists from endocrinology, magnetic resonance (MR) research and geriatrics who are experts in brain metabolism in T1DM, development of MR methodology, clinical implementation of artificial pancreas systems, and recruitment, assessment and retention of older persons.